Assessment of the Amorphous "Solubility" of a Group of Diverse Drugs Using New Experimental and Theoretical Approaches
Assessment of the Amorphous "Solubility" of a Group of Diverse Drugs Using New Experimental and Theoretical Approaches
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DOI：
10.1021/mp500571m
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发表时间：
2015-02-01
影响因子：
4.9
通讯作者：
Taylor, Lynne S.
中科院分区：
文献类型：
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作者：
Almeida e Sousa, Luis;Reutzel-Edens, Susan M.;Taylor, Lynne S.
难溶化合物的过饱和潜力在用于提高生物利用度的增溶制剂的背景下是有意义的。在这方面，非晶态的溶解度，即相对于晶型可以获得的溶液浓度的最大增量，是一个重要的参数，尽管这是一个很难通过实验评估的参数。目前研究的目标是开发新的方法来确定无定形溶解度，并将实验值与理论预测值进行比较。使用溶剂交换法对一组不同的模型化合物进行了评估，以原位生成非晶相，确定形成非晶态材料的浓度。非晶态溶解度的理论估算是基于晶相和非晶相的热性质、晶态溶解度和水饱和非晶相中水的估计浓度。所有六种化合物都可以瞬间捕获无定形沉淀的形成，从而通过实验确定无定形的溶解度。实验非晶态溶解度与理论计算值的比较表明，特别是当理论估算方法将析出相视为过冷液体并考虑了两种形式之间的热容差异时，两者之间的一致性很好。在水中的最大过饱和度比高度依赖于化合物，布洛芬为4，索拉非尼为54。这一信息可能有助于预测以无定形固体分散体或其他依赖过饱和的配方配制的难溶化合物的生物暴露情况的改善。
The supersaturation potential of poorly water-soluble compounds is of interest in the context of solubility enhancing formulations for enhanced bioavailability. In this regard, the amorphous solubility, i.e., the maximum increase in solution concentration that can be obtained relative to the crystalline form, is an important parameter, albeit a very difficult one to evaluate experimentally. The goal of the current study was to develop new approaches to determine the amorphous solubility and to compare the experimental values to theoretical predictions. A group of six diverse model compounds was evaluated using the solvent exchange method to generate an amorphous phase in situ, determining the concentration at which the amorphous material was formed. The theoretical estimation of the amorphous solubility was based on the thermal properties of the crystalline and amorphous phases, the crystalline solubility, and the estimated concentration of water in the water-saturated amorphous phase. The formation of an amorphous precipitate could be captured transiently for all six compounds and hence the amorphous solubility determined experimentally. A comparison of the experimental amorphous solubility values to those calculated theoretically showed excellent agreement, in particular when the theoretical estimate method treated the precipitated phase as a supercooled liquid, and took into account heat capacity differences between the two forms. The maximum supersaturation ratio in water was found to be highly compound dependent, varying between 4 for ibuprofen and 54 for sorafenib. This information may be useful to predict improvements in biological exposure for poorly water-soluble compounds formulated as amorphous solid dispersions or other formulations that rely on supersaturation.